Local-Regional Recurrence of Pheochromocytoma/Paraganglioma: Characteristics, Risk Factors and Outcomes

Objective To study the characteristics, risk factors, and outcomes of local-regional recurrence of pheochromocytoma and paraganglioma (PPGL). Methods Clinical data of 96 PPGL patients with local-regional recurrence and 112 patients without recurrence were retrospectively analyzed. Results Recurrent patients exhibited a median recurrence time of 6.0 (4.0, 9.0) years after resection of the primary tumor. SDHB mutation [HR 4.1 (1.7, 9.5), p=0.001), primary tumor size ≥5cm [HR 2.3 (1.1, 4.7), p=0.028], and average Ki-67 count ≥3% in the primary tumor [HR 2.6 (1.4, 4.9), p=0.003] were independent predictors for recurrence of PPGL. Primary tumor sizes ≥5cm [HR 5.1 (1.7, 15.3), p=0.003] and average Ki-67 counts ≥3% of the primary tumor [HR 2.4 (1.1, 5.2), p=0.035] were independent predictors for recurrence of pheochromocytoma, while SDHB mutation [HR 4.6 (1.5, 13.9), p=0.007] was a predictor for paraganglioma recurrence. Among recurrent patients, 47% (45/96) had multiple nodules in recurrent sites, and 58% (56/96) had metastases, with 20% (19/96) being implantation metastases. The risk of metastases (42% vs. 25%, p=0.030) and death (15% vs. 8%, p=0.003) was significantly increased in untreated patients after recurrence compared with treated patients. Conclusion Long-term follow-up is necessary for all PPGL patients. Risk factors for recurrence of pheochromocytoma and paraganglioma differ, with primary tumor size and average Ki-67 count representing independent predictors for pheochromocytoma patients and SDHB mutations predicting paraganglioma recurrence. Although the treatment of recurrence can be difficult, patients should be treated once recurrence is detected as it decreases the risk of metastases and death.


INTRODUCTION
Pheochromocytoma (PHEO) and paraganglioma (PGL), together referred to herein as PPGL, are rare neuroendocrine tumors arising from chromaffin cells of the adrenal medulla and extra-adrenal autonomic paraganglia, respectively. The incidence of PPGL is approximately 0.6 cases per 100,000 personyears (1). Once PPGL is diagnosed, surgery is the mainstay of treatment. Long-term follow-up is recommended for patients who have undergone surgery as even tumor-free patients are at risk of recurrence and metastases. Recurrence after resection is reported to occur in 3-16% of patients (2)(3)(4)(5)(6)(7) and can be difficult to treat, especially if diagnosis is delayed. So far, few studies focused on the characteristics of localregional PPGL recurrence, all which were small scale studies (2,3,7). The aim of this study was to study the characteristics, risk factors, and outcomes of local-regional recurrence of PPGL. The data presented in this article represents the largest study of PPGL recurrence to date.

Patients
We retrospectively studied clinical data of 96 patients diagnosed with local-regional recurrent PPGL in Peking Union Medical College Hospital, China. Local-regional recurrence referred to a reappearance of disease at the original site with or without metastases after complete surgical resection of the original tumor which had been confirmed by negative biochemical and imaging tests. Radiological features of local recurrence were often irregular in shape and closely adhered to surrounding tissues, and may be multiple nodules fused together. The recurrence-free survival was defined as the time elapsed from initial surgery until recurrence. Patients with metastases at onset, failure of complete resection of the primary tumor or new lesions which were not located at the original site of disease were excluded. We also retrospectively analyzed clinical data of 112 patients without recurrence with a median follow-up time of 8.0 (7.0, 9.8) years to study risk factors for recurrence. Patients without local-regional recurrence referred to those patients without recurrence or metastasis after complete resection of the primary tumor during the entire follow-up. Metastases were defined in accordance with the 2017 WHO classification of endocrine tumors. Metastases-free survival was defined as the time elapsed from initial surgery until metastasis. Clinical data, including gender, age at diagnosis, recurrence and metastases, symptoms, blood pressure (BP), primary tumor location, the maximum diameter of primary tumor, tumor secretion function (24-hour urinary catecholamine excretion), primary tumor pathology, genetic characteristics, treatment, and prognosis of recurrence were collected. The study was approved by the Institutional Review Board of Peking Union Medical College Hospital(S-K431). Written informed consent was obtained from all included patients.

Statistical Analysis
All statistical analyses were conducted using Statistical Product and Service Solutions, version 21.0. Categorical data are presented as frequencies and percentages. Normally distributed data are expressed as mean ± standard deviation (x ± s). Non-normally distributed data are presented as median and quartile range (25%, 75%). The association between two independent samples with a normal distribution was determined using independent sample T tests, while the association between two independent samples with a non-normal distribution was assessed using Wilcoxon rank sum tests. Associations between two dichotomous parameters were evaluated utilizing the Chi-square test. Kaplan-Meier testing was employed to describe progression-free recurrence. Factors validated in univariate analysis were further tested in multivariate analysis using Cox proportional hazard models. Results are reported as hazard ratios (HR) with 95% confidence intervals. All tests were conducted two-sided, with P values< 0.05 being considered statistically significant.

DISCUSSION
Recurrence of PPGL after resection occurred in 13.3% patients who were followed up for more than five years after tumor resection in our center (unpublished data). A recent systematic review showed that the overall rate of recurrent PPGL was 0.98 events/100 personyears, which suggested the risk of recurrence after complete resection was previously underestimated (9). In a meta-analysis of 13 studies, the mean time to recurrence was approximately 4 years (0.5-12) (6). In our study, recurrent patients exhibited a median recurrence time of 6.0 (4.0, 9.0) years after resection of the primary tumor, which is longer than previous reports (2,6). Our data suggest that the follow-up of all patients after tumor resection should be at least 10-20 years, as recurrences may occur after a prolonged time after initial treatment. In our study, we found SDHB mutation, primary tumor sizes ≥5cm, and average Ki-67 counts ≥3% in the primary tumor were independent predictors of recurrence. The results in our study were similar to previous reports (3,7,(10)(11)(12)(13). Moreover, we separately studied the predictors of PHEO and PGL, and found that the risk factors for recurrence of PHEO and PGL were different. The risk of recurrence was 5.1-and 2.4-fold higher in PHEO patients with primary tumor sizes≥ 5cm and average Ki-67 counts ≥3%, respectively. SDHB mutations were predictors for recurrence in PGL patients and not for PHEO, with the risk of recurrence being 4.6 fold higher in PGL patients with SDHB mutation than those without. Recent studies have shown that higher Pheochromocytoma of the Adrenal Gland Scaled Score (PASS) and Grading system for Adrenal Pheochromocytoma and Paraganglioma(GAPP) score were significantly associated with recurrence, and it was, respectively, 1.2-and 3.4-fold higher in patients with higher PASS and GAPP scores (13,14). In our study, 19 patients unfortunately exhibited implantation metastases which are considered to be related to tumor cells scattered in peritoneal cavity during surgical resection (15). The initial surgery of most patients was not performed in our hospital. Laparoscopic surgery may be more challenging if the tumor is large since these tumors more likely to be broken and tumor cells scattered when manipulated. The guideline recommends open resection for large (>6 cm) PHEO and PGL to ensure complete tumor resection, preventing tumor rupture and avoiding local recurrence (16). However, several studies have suggested that larger PPGL may be amenable to laparoscopy with safety levels similar to those for smaller tumors (4,17). Here, we did not find that laparoscopic surgery can increase the risk of recurrence. The key to preventing implantation metastases is an endocrine surgeon with expertise in laparoscopic techniques and operating on PPGL. Furthermore, in cases of tumor rupture during surgical resection, careful follow-up is mandatory.
Recurrence is difficult to treat especially if diagnosis is delayed. Unfortunately, surgery was not an option in 43% of recurrent patients included in this study. Several reasons can lead to difficulty of recurrence treatment, for instance, 47% recurrent patients had multiple nodules in recurrent site in our study, recurrent patients were often accompanied by metastases, 58% had metastases in our study (7). Although treatment of recurrences is challenging, patients should be treated as soon as possible after detection of recurrence as we found that treatment significantly decreased the risk of metastases and death compared to untreated patients. There were some limitations in our study. Firstly, localregional recurrence referred to a reappearance of disease at the original site after complete surgical resection which had been confirmed by negative biochemical and imaging tests. However we cannot completely exclude the situation that a separate, metachronous PPGL arising in the same location. Another weakness of our study was the lack of PASS/GAPP scores which may be beneficial to predicting tumor recurrences.

CONCLUSION
Long-term follow-up in all PPGL patients is necessary. PHEO patients with primary tumor sizes ≥5cm, average Ki-67 counts ≥3%, and PGL patients with SDHB mutation exhibited an elevated risk of recurrence. Recurrence is difficult to treat as it is often accompanied by multiple nodes in recurrent sites, distant metastases, and implantation metastases, however it is recommended as it can reduce the risk of further metastases and death.

DATA AVAILABILITY STATEMENT
The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

ETHICS STATEMENT
The study was approved by the Institutional Review Board of Peking Union Medical College Hospital(S-K431). Written informed consent was obtained from the patients included.

AUTHOR CONTRIBUTIONS
YC performed the study and drafted the manuscript. AT contributed to the concept and design for the study. YG, XM, SC, and LL contributed to the manuscript preparation. XC prepared histopathological results. All authors contributed to the article and approved the submitted version.